Scorned Thalidomide Raises New Hopes

By SANDRA BLAKESLEE

Published: April 10, 1990

THALIDOMIDE, the notorious tranquilizer that was pulled from the market when women who took it gave birth to severely deformed infants, is finding new life. Researchers have discovered that it is a spectacularly effective agent for combatting rejection of foreign tissue and for alleviating the symptoms of several diseases in which the immune system turns against the body.

But researchers say the drug's reputation may frighten researchers and patients away from it.

Physicians have been using the drug for almost 25 years for treating a complication of leprosy involving the immune system. New human clinical trials of thalidomide for other immune disorders are under way in the United States and at several laboratories in Latin America, Canada and Australia. The drug is also being tested in animals at organ transplant centers in the United States.

Researchers say thalidomide is more effective than cyclosprorin and less toxic than steroids, the major drugs used in transplant medicine.

Despite thalidomide's promise as an agent for suppressing the immune system, scientists involved in the research say it has been extremely difficult to persuade drug companies, physicians and government agencies to cooperate in the experiments.

'It's Taboo,' One Scientist Says

Once sold as a sleeping pill, thalidomide caused severe limb deformities in nearly 12,000 European children born in the late 1950's and early 1960's. The drug was never approved for use in the United States.

''Even if it turns out to be a great drug, I don't think thalidomide will ever receive widespread usage'' in the United States and Europe, said Dr. Kenneth I. Kaitin, assistant director of the center for drug development at Tufts University School of Medicine in Boston. ''It's taboo. Thalidomide changed drug regulatory processes throughout the world. Most doctors won't even discuss it.''

For a variety of historical and medical reasons, Dr. Kaitin said, researchers in Central and Latin American are less leary of the drug. A Brazilian company is a major supplier of thalidomide to researchers in the United States.

The Food and Drug Administration now defines thalidomide as an orphan drug, one that can be used to treat rare human diseases, said Dr. Georgia B. Vogelsang, an assistant professor of oncology at Johns Hopkins School of Medicine in Baltimore. As an orphan drug, thalidomide is being used to treat leprosy and a dangerous consequence of bone marrow transplants called graft-versus-host disease.

Effects Noted in 1960's

Thalidomide was recognized as an immunosuppressive agent about the same time that it was pulled off the world market for causing birth defects, in the early 1960's, said Dr. Vogelsang. An Israeli researcher gave the drug to patients with a severe form of leprosy that involved the immune system and made victims agitated. The drug not only sedated patients, said Dr. Vogelsang, ''it made their disease get better.''

Researchers in several countries continued sporadic experiments with thalidomide as a treatment for leprsoy and other immune disorders, she said. ''Reports appeared in offbeat places like the Ethiopian Medical Journal,'' she said. ''After seeing its effects in patients, nurses in leprosariums began taking it to treat their own autoimmune diseases like lupus erythematosus, Crohn's disease and arthritis.''

In 1983, a researcher who had done research on thalidomide, Dr. Gary Gordon, joined the Johns Hopkins faculty amd told Dr. Vogelsang about its potential uses in treating immune disorders. They decided it was worth investigating.

Dr. Vogelsang's specialty, graft- versus-host disease, afflicts half of all 2,000 patients receiving bone marrow transplants to treat cancer each year in the United States. White blood cells within the transplanted marrow literally reject and attack the patient's own tissues in a manner similar to most autoimmune diseases. Half of those who develop the disease die from it.

Success With Animals

Animal experiments showed that thalidomide was ''the only agent that can rescue an animal from the disease'' once the rejection process has started, said Dr. Vogelsang. ''It is better than cyclosporin. Its effects are more permanent and it is less toxic,'' she said.

In 1987, Dr. Vogelsang and her colleagues began giving thalidomide to selected patients with a chronic form of graft-versus-host disease after they failed to respond to conventional treatment. The transplant procedure leaves patients sterile, so there is no worry about birth defects, she said. The only side effects are sleepiness, mild constipation and, in one instance, a tingling of fingers and toes, the side effect that prevented it from being sold in the United States.

Of 100 people treated at Hopkins and a few other centers worldwide, she said, 55 to 60 have responded very favorably. Among those who did not respond, she said, at least half could not absorb the drug.

Thalidomide is the standard treatment for a severe complication of leprosy that affects half of the patients in the United States, said Dr. Robert C. Hastings, chief of laboratory research at the National Hansen's Disease Center in Carville, La. The body mounts an inappropriate immunologic response to dead bacteria that cause leprosy, he said, and begins to attack all tissues in which the bacteria are living.

'It's a Magical Drug'

Thalidomide brings the problem under control within 24 hours in 95 percent of patients, said Dr. Hastings. ''It's a magical drug,'' he said. About 350 patients have been treated each year with thalidomide since 1966, he said. Fertile women are not allowed to take the drug unless they reside at the Carville Center, use birth control pills, undergo a weekly pregnancy test and record menstrual periods while undergoing treatment. Physicians also watch for possible signs of nerve damage, but so far it has not been a problem, said Dr. Hastings.

Encouraged by thalidomide's effects on the immune system, researchers are conducting animal experiments to see if the drug might combat rejection of hearts, kidneys and other solid organs. Dr. Vogelsang said that the research ''looks very promising.''

There is quite a bit of experimentation with thalidomide in Latin America, said Dr. Kaitin. A Colombian researcher has shown it that alleviates the symptoms of rheumatoid arthritis. It is also being used successfully to treat several skin diseases.

Researchers say they still do not know exactly how thalidomide causes human birth defects but that it should be possible to design a form of the drug that does not cause physical abnormalities in a developing embryo.

Because of the drug's reputation, no American drug company manufactures it, Dr. Vogelsang said. One company, the Andrulis Research Corporation in Besthesda, Md., provides leprosy researchers with a partly processed form of thalidomide that is defined as a chemical and not a drug. The researchers refine the product into its medically useful form.

Dr. Vogelsang gets her thalidomide from a company in Brazil and forwards it to other interested researchers in the United States. A German company continues to manufacture the drug for leprosariums in third world countries.